PXD023424

PXD023424 is an original dataset announced via ProteomeXchange.

Title	USP25 is a HIF-1 regulator and a therapeutic target in pancreatic ductal adenocarcinoma
Description	Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with both an extremely poor prognosis and response to conventional chemotherapy. Identifying novel biological vulnerabilities is therefore critical in the development of more effective therapies. By using patient-derived organoids and murine genetic models, we developed a pipeline for identifying biologically active deubiquitylases (DUBs) with activity-based proteomics, coupled with a loss-of-function genetic screen in organoids. We found that ubiquitin specific protease 25 (USP25) is indispensable for PDAC progression. Compared with normal pancreatic tissue, USP25 was highly expressed and active in murine PDAC tumours and in primary human PDAC samples. Silencing of Usp25/USP25 led to reduced tumour organoid formation and viability, and transcriptional profiling revealed that USP25 is a regulator of hypoxia, glycolysis and HIF-1 signalling pathways. Mechanistically, we found that USP25 directly interacts with HIF-1 and that its deubiquitylase activity regulates HIF-1 protein stability, nuclear translocation and transcriptional activity. Moreover, treatment with a novel USP25 inhibitor resulted in a dramatic loss of murine and patient-derived organoid viability, HIF-1 signalling, and consequently induced substantial regression of murine and human organoid-derived xenografts in vivo. Thus, USP25 is a promising therapeutic target for the treatment of human PDAC.
HostingRepository	PRIDE
AnnounceDate	2022-05-19
AnnouncementXML	Submission_2022-05-19_14:17:33.455.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Steven Howell
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-01-06 00:03:43	ID requested
⏵ 1	2022-05-19 14:17:35	announced

Nelson JK, Thin MZ, Evan T, Howell S, Wu M, Almeida B, Legrave N, Koenis DS, Koifman G, Sugimoto Y, Llorian Sopena M, MacRae J, Nye E, Howell M, Snijders AP, Prachalias A, Zen Y, Sarker D, Behrens A, USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer. Nat Commun, 13(1):2070(2022) [pubmed]

submitter keyword: Human, Mouse, pancreas, cancer, deubiquitylase, biotin, affinity, LC-MSMS

James McCrae
contact affiliation	Acting Head of Proteomics
contact email	James.MacRae@crick.ac.uk
lab head
Steven Howell
contact affiliation	Francis Crick Institute
contact email	steven.howell@crick.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/05/PXD023424

PRIDE project URI

• PRIDE
  1. PXD023424
     1. Label: PRIDE project
     2. Name: USP25 is a HIF-1 regulator and a therapeutic target in pancreatic ductal adenocarcinoma